Weener schtjlemann



Patented June 24, 1930 UNHTEI STATES PATENT OFFICE VWERNERHSCHULEMAINN, or VOHWINKEL-HAMMERSTEIN, AND AUGUST WINGLER AND Fnrrz MIE'rzscH, or; ELBERFELI), GERMANY, ASSIGNOBS T WINTHROP CHEMICAL COMPANY, INC., or NEW YORK, N. Y.

PHARMACEUTICAL PRODUCT No Drawing. Application filed August 24, 1925, Serial No. 52,228, and in Germany September 11, 1924.

The present invention relates to new compounds of the diazine, oxazine, thiazine, vacridine and Xanthene series, i. e., the series including aromatic compounds containing the grouping wherein X represents hydrogen, an alkyl group, or other monovalent substituent, R an alkylene residue, R hydrogen or an alkyl, R an alkyl group.

. i We have discovered that these compounds generally possess valuable pharmaceutical properties. 7

The manufacture of our new compounds can be effected in several ways; for instance,

an amino derivative of a compound of one of the above mentioned series may be caused to be acted upon by an aminoalkylhalogenide having the general formula:

wherein Y represents a halogen atom, R an alkylene residue, R hydrogen or an alkyl group, R an alkyl group or an aminoalkyl group. Instead .of the aminoalkylhalogenide one may use in this process the salt of an aminoalkylhalogenide with an inorganic acid or a substitution product of the aminoalkylhalogenide such as the bromoethylphthalimide. In the last case phthalic acid is to be split off subsequently.

The manufacture of our new compounds can be furthermore efiected by converting such amino compounds as are suitable intermediate products for the manufacture of amino derivatives of the above mentioned series 1nto aminoalkylaminoderivatives and wise the side-chain carrying the aliphatic nitrogen, whet-her occurring only once or several times, may be either straight or branched and the aliphatic nitrogen atom may happen tobe in the ,8 or -y position or even further removed from the aminogroups in the said amino derivatives.

line are heated under reflux for 12 hours with 135 parts by weight of diethylaminoethyl chloride in 800 parts by weight of dry benzene. The hydrochloride of d1ethyl-am1no-' ethyl-aniline thus produced is filtered off, washed with a little benzene, dissolved in water, precipitated as the free base with potassium carbonate and dissolved in a little benzene for the purpose of eliminating any quaternary ammonia compoundwvhich may have been salted out. After drylng the base withpotassium carbonate it distils as a colorless liquid of boiling point 121123 C. at

Earample 2 For the manufacture of N-methyl-diethylaminoethylaniline 107 parts by weight of methylaniline are heated under reflux for 24 hours with 135 parts by weight of diethylaminoethylchloride in 250 parts by weight of dry benzene. The hydrochloride of methyldiethylaminoethylaniline which separates is worked up as in Example 1. The free base, a colorless liquid, distils at 124126 C. at 5 mm. pressure, with Very little preliminary distillation of volatile impurity.

The same compound is obtained by first converting Inonomethylaniline into hydroxyethyl-methylaniline by treatment with chloroethyl alcohol or ethylene oxide, transforming this compound into chl0roethyl-methylaniline by the action of thionyl chloride and thereupon substituting the chlorine by the diethylamine radicle by means of diethylamine. Methyldiethylaminoethylaniline obtained by this method possesses the same boiling point of 124126 C. at 5 mm. pressure as the product of the previous reaction.

The manufacture of the corresponding dyestuff is effected in exactly the same manner as in Example 1. The new dyestuif after being freed from zinc is a lustrous bronze powder, easily soluble in water and of a blue shade.

Example 3 For the manufacture of N-methy-adimethylamino-B-methyl-y-butylaniline 107 parts by weight of methyl-aniline are heated for about 24 hours at 110120 G. with 200 parts by weight of the hydrochloride of ozdimethylamino-,8-methyl- -chlorobutane, until the completely solidified melt which is finally formed has become entirely soluble in water. The reaction product is dissolved in water and the solution is rendered alkaline With potassium carbonate. The free base which separates is further treated as in Example 1. It distils as a colorless liquid at 133135 C. at 6 mm. pressure, after the first runnings of methylaniline have distilled off. Precisely the same compound can be obtained by boiling methylaniline with the adimethyl-amino-B-methyl- -chlorobutane for 30 hours in benzene solution. This compound can be converted in the customary manner, with the intermediate production of the pnitroso-compound, into p-amin0-N-methyl-udimethyl amino B methyl y butylaniline. The corresponding thiazine dyestuff is prepared from the latter compound using dimethylaniline instead of p-aminodimethylaniline, following the same procedure as described in Example 1.

The dyestufl", after being freed from zinc 'is a lustrous dark blue powder, easily soluble in water and of a blue shade.

The customary methods for the manufacture of oxazines and diazines can be success fully applied to the above described amines, their nitrosoand p-amino-derivatives, the respective oxazine and diazine derivatives being produced with satisfactory yields. Instead of the herein described polyamines, other amines of similar constitution can be employed, such for example as the piperidine compounds. Thiazines, oxazines, diazines, acridines, etc., containing free amino groups, likewise yield polyamino compounds by the application in the appropriate manner to the final compounds of the methods described herein for use only with primary and secondary arylamines. If hydroxylated arylamines are selected as the starting material for the manufacture of polyamines, it is also possible to obtain by the application of the customary methods, compounds belonging to the Xanthene series. Thus 011 melting N-diethylamineethyl methyl-m aminophe- 1101 with phthalic acid, compounds of the rhodamine series are produced.

The following are further methods of execution of the processes for which we claim protection E sample 4 \CHQ.CIIZN(CQII5)Z Molecular proportions of a-aminoacridine and the hydrochloride of diethylaminoethyl chloride are melted together in a closed vessel and the temperature is maintained for 7'8 hours at 110120 C. The product of the reaction is dissolved in warm dilute hydrochloric acid and filtered from an insoluble dark colored material. The new base is salted out from the filtrate by ;-means of potassium carbonate, extracted with ether and after. distilling off the ether it is puri-.

fied by distillation in a high vacuum. The product is a viscous golden yellow oil which boils at 215 C. under ,1 mm. pressure. It is soluble in ether and forms with ethereal hydrochloriciacid a faintly violet colored hygroscopic'diacid -salt, which is readily soluble in water with a weak wine-red coloration. I I v The t-aminoacridine of'a melting point 105'106 C. and boiling under 1 mm. -at 183-184? C. is produced by reduction of l -nitroac'ridine with stannouschloride and hydrochloric acid. The nitro-compound is most advantageously prepared by the condensation of o-bromonitrobenzene and 0- aminobenzaldehyde, ring formation being effected by the action of concentrated sulfuric acid. Another method for the manufacture of -aminoacridine was described recently by Clemo Perkin Jr. and Robert Bobinson J. O. s. 125, 1751 (1924).

E wample 5 I) N N /H \OHa-OH -NQ Eh);

diacid salt with hydrochloric acid, which dissolves readily in water with a weak yellow coloration.

'2-methyl-4-aminoacridine melting point 111 C. boiling point 197 C. under 1 mm. pressure is prepared according to either of the two methods outlined above and crystallizes frombenzine, ether, alcohol, oracetone in brightyellow prisms or needles.

3.6 -diaminoacridine is dissolved in to 40 timesthe amount of cyclohexanol at about 120 C. the solution is carefully cooled to 0., whenthe'mole'cular quantity of diethyls aminoethyl chloride is added and stirring is continued for 2 days at 90 C. After cooling the. separated hydrochloride is dissolved in the minimum amount of water and fractionally precipitated with concentrated ammonia. The yellow base, which easily crystallizes on rubbing the sides of the vessel, posse'ssesthe above formula and is distinguished from the starting compound'by its greater solubility in water and by the property of being precipitated by ammonia with great er difiiculty.

Asimilar product is obtained by dissolving 3.6-diaminoacridine in alcohols, e; g. amyl alcohol, treating with the molecular quantity of sodium acetate, and if necessary a little copper salt and stirring for several hours with the molecular quantity of diethylaminoethyl chloride at about 100 C. The liquid is filtered hot and on cooling, a little of theunattacked starting material separates; the solution is thereupon rendered acid with hydrochloric acid, the amyl alcohol is blown off and the aqueous solution is then concentrated, when the hydrochloride of the new base will crystallize. It is converted into the above mentioned base by dissolving in the minimum quantity of water and precipitating withan excess of strong ammonia.

, Example 7 For themanufacture of m-amino-mono-N- diethylaminoethyl-aniline100 grams. of miron filings and acetic acid. The. reduced are stirred together, and the whole is slow- 1 After the elimination of the benand salted out with common salt.

and sodium carbonate solution in a. separat- K base.

ing funnel, whereby the zinc free base is dissolved by the nitrobenzene, from which it can be again extracted with dilute hydrochloric acid. The solution is evaporated in vacuo, when the dyestuff remains as a brownhygroscopic powder, very readily soluble in water with a pure yellow coloration.

E mample 5 coon the nitrobenzene with dilute hydrochloric acid. The acid solution is evaporated to dryness in vacuo, when the dyestuii' remains as a reddish brown, hygroscopic powder,

which dissolves very readily in water with a and COOO Ha For the manufacture of m-hydroxy-N- diethylamino-ethyl-ethylaniline 102 grams of m-hydroXy-N-ethylaniline are dissolved in 150 cc. of benzene on the water bath, 100 grams of diethyla1nino-ehtyl chloride in 150 cc. of benzene are added and the whole heated to boiling for a day. On cooling, the benzene is decanted and the free base is liberated from the aqueous layer by the addition of potassium carbonate and extracted with benzene. After the elimination of the benzene the new base distils as a highly retracting liquid of boiling point 180-182 C. under 4 mm. pressure. At first it forms a viscous oil, but on standing for several days it solidifies to a. white crystalline mass.

For the preparation of the corresponding dyestuff 40 grams of the base are heated on an oil bath with constant stirring with grams of phthalic acid anhydride for 3-4 hours to a maximum temperature of 175 C. After cooling, the brittle solidified melt is powdered and advantageously dissolved in nitrobenzene at 80 C. The solution is extracted several times with sodium carbonatesolution at 4050 C. in order to eliminate phthalic acid and to liberate the color The latter is thereupon extracted from terial by a slightly yellower coloration of the solution in water. However, the corresponding dyestufi base is characterized as compared with the unesterified base by its very ready solubility in nitrobenzene, as well as by the startlingly much more violet coloration in nitrobenzene.

Example 9 freed from zinc with sodium carbonate. It is a bronze powder soluble in water with a blue coloration.

E mample 10 Two molecules of m-hydroXy-N-(diethylamino-et-hyl-methyl)-aniline are boiled together with two molecules of a 50 per cent aqueous oxalic acid and one molecule of formic aldehyde in alcoholic solution during 24 hours, water is added, and the diphenylmethane compound is salted out, dissolved in benzene and the benzene is distilled off. The residue is introduced Whilst cooling into 4 parts by weight of concentrated sulfuric acid and the yellowish-brown solution is heated on the water bath. 27 C. and oxidized by adding dried sodium nitrite at 27-30 C. whilst stirring. The acid solution is poured-on ice and the zinc chloride salt of the dye is isolated, purified and freed from zinc.

We claim 1. A process of making therapeutically valuable derivatives, comprising reacting upon an amino derivative of an aromatic compound of the series containing the grouping wherein one A represents an element of the group N, S, and O, and the other A represents an elementof the group C and N, with an aminoalkylhalogenide compound of the general formula /R2 YR1N\R3 wherein Y represents a halogen atom, R an alkylene residue; R represents hydrogen or an alkyl group and R stands for an alkyl group.

2. As new products aromatic compounds containing the grouping wherein one A represents an element of the group N, S, and O, and the other A represents an element of the group C and N, and substituted by the group:

wherein X represents hydrogen, an alkyl It is allowed to cool to azine series substituted by the group:

R: NR1N R3 wherein X represents hydrogen, an alkyl group, or other monovalent substituent, R an alkylene residue, R hydrogen or an alkyl group and R an alkyl group.

4. As new products compounds of the thiazine series substituted by the group:

wherein X stands for hydrogen or an alkyl group, R for an alkylene residue, R and R for methyl or ethyl groups.

5. As new products compounds of the general formula:

wherein Y stands for an acid radicle, X for hydrogen or an alkyl group R for an alkylene residue possessing at least two but not more than five carbon atoms, R and R for methyl or ethyl groups.

6. As new products compounds of the general formula:

wherein Y stands for an acid radicle, X for hydrogen or methyl.

7. As a new product the compound of the general formula:

which in a dry state is a bronze-colored pow der, easily soluble in water.

In testimony whereof we have hereunto set our hands.

WERNER SCHULEMANN. AUGUST WINGLER. Y FRITZ MIETZSCH. 

